Precutaneous absorption accelerator and preparation containing same

ABSTRACT

A percutaneous absorption accelerator and a precutaneous absorbent preparation containing the same and, more particularly, a percutaneous absorption accelerator containing ether derivatives of specific glycerols or polyglycerols and alcohols as effective components and a percutaneous absorbent preparation containing the percutaneous absorption accelerators and pharmaceutically effective components.

This application is a continuation of Ser. No. 047,513 filed May 6, 1987now abandoned which is a continuation of Ser. No. 726,320 filed Apr. 23,1985 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a percutaneous absorption acceleratorand a percutaneous absorbent preparation containing the same, and moreparticularly, to a percutaneous absorption accelerator containing etherderivatives of specific glycerols or polyglycerols and alcohols as theactive ingredients and percutaneous absorbent accelerators andpharmaceutically effective components.

As methods for administration of drugs, oral administration, rectaladministration, intracutaneous administration, and so forth have beengenerally adopted. Among these, oral administration has been widelyemployed. However, in the case of oral administration, certaindifficulties have been encountered due to side effects such asgastrointestinal disturbances, anorexia, vomitting, and abdominal pain.In addition it is necessary in most cases to administer large quantitiesof these drugs. In recent years, preparations for percutaneousadministration have been developed, some have been for, commercial use,in hopes that the side effects would be minimized and the desiredpharmacological effects would occur more safely. In many cases, however,percutaneo absorbability of pharmaceutically effective components insuch preparations are unsatisfactory and the purposes have beensatisfactorily achieved only with difficulty. Namely, skin and itskeratin layer (which constitutes the outermost layer) functionsphysiologically and acts as a protective wall against permeation ofsubstances into the body. In many cases, it is difficult for a basealone, used for conventional topical agents, to attain percutaneousabsorption sufficient for the pharmaceutically components formulatedtherein to be effective. For this reason, a device is necessary tocontrol the permeability of drugs through the keratin layer of the skinand enhance the percutaneous absorption of drugs.

In addition, for accelerating absorption of pharmacologically activesubstances from the mucous portions of the human body, such as themucous membrane of the eye, nasal mucous membrane, bucal mucousmembrane, vaginal mucous membrane, rectal mucous membrane, improvementof the preparation form, improvement of bases, formulation of compoundshaving an absorption acceleration effect, and the like have been made.Among them, the improvement of the preparation form and the improvementof bases are possible to a certain extent; however, epochmakingimprovement is not expected and the target of research has been focusedon the search for and application of compounds having an absorptionaccelerating effect.

For such purposes, it has generally been known to formulate a so calledpercutaneous absorption accelerator in a base. As such absorptionaccelerators, there are known dimethyl sulfoxide; amide compounds suchas dimethyl acetamide, dimethylformamide, and N,N-diethyl-m-toluamide,azacycloalkan-2-one derivatives, such as 1-dodecylazacyclo-heptan-2-one;esters of alcohol and carboxylic acids, such as isopropyl myristate,isopropyl palmitate, diethyl sebacate, and diisopropyl adipate; andcrotonyl-N-ethyl-o-toluidine. However, these absorption acceleratorshave been found to be unsatisfactory in their absorption acceleratingeffect and, in many cases, practical pharmacological effects cannot beobtained. In addition, these pharmacological effects cannot be obtained.Moreover, these absorption accelerators involve problems in practicaluse because the absorption accelerators themselves show irritation tothe skin and corrode synthetic resins due to their property as potentsolvents to dissolve irritative substances, and sensitized substancesout of containers for drugs, clothes, and accessories, so that generaladaptation and use are restricted.

SUMMARY OF THE INVENTION

Therefore, in accordance with the present invention it has been foundthat by formulating specific ether derivatives of glycerols orpolyglycerols as percutaneous absorption accelerators in a base,percutaneous absorption of pharmaceutically effective components can bemarkedly increased and the pharmacological effects of thepharmaceutically effective components can be demonstrated effectivelyand safely.

DETAILED DESCRIPTION

Namely, the present invention provides percutaneous absorptionaccelerators comprising ether compounds of glycerols or polyglycerolsand alcohols (hereafter simply referred to as "ether derivatives") asessential components and, percutaneous absorbent preparations containingpharmaceutically effective components and the percutaneous absorptionaccelerators. The term percutaneous absorption in the present inventionmeans the absorption through a mucosal portion of the human body, suchas the mucous membrane of the eye, nasal mucous membrane, buccal mucousmembrane, vaginal mucous membrane, rectal mucous membrane, and the likein addition to the topical percutaneous absorption through the keratinlayer of the skin.

The ether derivatives used in the present invention are obtained byreacting alcohols with glycerols or polyglycerols derived therefrom in aconventional manner. Specific examples of alcohols which are usedinclude straight chain type aliphatic alcohols, such as methyl alcohol,ethyl alcohol, propyl alcohol, butyl alcohol, octyl alcohol, decylalcohol, dodecyl alcohol, hexadecyl alcohol, octadecyl alcohol, andoctadecanyl (oleyl) alcohol; branched type aliphatic primary alcohols,such as isopropyl alcohol, isobutyl alcohol, 2-ethylhexyl alcohol,2-heptylundecyl alcohol, 2-(1,3,3-trimethylbutyl) octyl alcohol,2-decyltetradecyl alcohol, 2-dodecylhexadecyl alcohol,2-tetradecyloctadecyl alcohol,5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl alcohol and methyl-brancedisostearyl alcohols represented by the following formula: ##STR1##wherein p represents an integer of 4 to 10; and q represents an integerof 5 to 11, and p+q represents 11 to 17 and has a distribution which isoptimum when p is 17 and q is 18; secondary alcohols, such as sec-octylalcohol, sec-decyl alcohol, and sec-dodecyl alcohol; tertiary alcohols,such t-octyl alcohol, and t-dodecyl alcohol; alicyclic alcohols such ascyclohexyl alcohol, and cyclopentyl alcohol; alkylphenols, such asoctylphenol, and nonylphenol.

Of the other derivatives used in the present invention preferred arethose represented by the following formula (I) or (II): ##STR2## whereinR₁, R₂, R₃ and R₄ (n numbers of R₄ may be the same or different) eachrepresents a hydrogen, a saturated or unsaturated straight or branchedaliphatic hydrocarbon group or aromatic hydrocarbon group having 1 to 24carbon atoms, provided that R₁, R₂, R₃ and R₄ (n times repeated) are notall hydrogen; and n represents an integer of 0 to 60.

In the ether derivatives represented by the formula (I) or (II), it ispreferred that R₁ to R₄ each be an aliphatic hydrocarbon having 1 to 18carbon atoms and the total carbon atoms of R₁ to R₄ be 4 to 36,preferably 8 to 12. Further, it is preferred that n be a number of 0 to60. Particularly preferred are those wherein n is 0 to 20, andpreferably 0 to 10. A more preferred combination of R₁ to R₄ and n isthe combination wherein n is 0 or 1 and the total carbon atoms of R₁ toR₄ are 4 to 36, particularly the combination in which n is 1 and thetotal carbon atoms of R₁ to R₄ is 8 to 22.

Of the ether derivatives (I) or (II), preferred examples includestraight chain primary alkyl glycerols, such as 1-O-n-octylglycerol,1-O-n-decylglycerol, 1-O-n-dodecylglycerol, 1-O-n-tetradecylglycerol,1-O-n-hexadecylglycerol, 1-O-n-octadecylglycerol, and1-O-n-octadecenylglycerol branched chain primary alkylglycerols, such as1-O-2-ethylhexylglycerol, 1-O-2-hexyldecylglycerol,1-O-2-heptylundecylglycerol, 1-O-2-octyldodecylglycerol,1-O-2-(1,3,3-trimethylbutyl)octylglycerol,1-O-5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octylglycerol, and 1-Omethyl-branched isostearylglycerols;

secondary alkylglycerols, such as 1-O-sec-octylglycerol,1-O-sec-decylglycerol, and 1-O-sec-dodecylglycerol; 1-O-alkylglycerols,such as 1-O-t-octylglycerol, 1-O-t-dodecylglycerol;1-O-alkyl-3-O-2',3'-dihydroxypropylglycerols such as1-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-3-O-2',3'-di-hydroxypropylglycerol,1-O-n-octadecenyl-3-O-2',3'-dihydroxypropylglycerol, and1-O-methyl-branched isostearyl-3-O-2',3'-dihydroxypropylglycerol;1,2-di-O-alkyl-3-O-2',3'-dihydroxypropylglycerols, such as1-O-n-octyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol, and1-O-methyl-branchedisostearyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;1,3-di-O-alkyl-2-O-2',3'-dihydroxypropylglycerols, such as1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-do-decyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-do-decyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-3-O-methyl-2-O- 2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-3-O-methyl-2O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-0-methyl-branchedisostearyl-3-0-n-butyl-2-0-2',3'-dihydroxypropylglycerol, and1-0-methyl-branchedisostearyl-3-0-n-octyl-2-0-2',3'-dihydroxypropylglycerol. The etherderivatives of glycerol or polyglycerol with these alcohols haveextremely low toxicity in LD₅₀ of 5000 mg/kg or more.

The percutaneous absorption accelerator of the present invention isprepared using the ether derivative of glycerol or polyglycerol withalcohols as it is, or by dissolving, dispersing or suspending the etherderivative of glycerol or polyglycerol with alcohols in a suitablesolvent such as water, ethanol, propylene glycol, triacetin, or thelike. Further, the percutaneous absorption accelerator of the presentinvention may be formulated, if necessary, with known compounds having apercutaneously absorbing property, for example, dimethylsulfoxide,dimethylacetamide, dimethylformamide, N,N-diethyl-m-toluamide,azacycloalkan-2-one derivatives, such as 1-dodecylazacycloheptan-2-one,esters of alcohols and carboxylic acids, such as isopropyl myristate,isopropyl palmitate, diethyl sebacate, and diisopropyl adipate,crotonyl-N-ethyl-o-toluidine, and the like.

The percutaneous absorbent preparation of the present invention may beformulated by incorporating various pharmaceutically effectivecomponents with the percutaneous absorption accelerator. Thepercutaneous absorption accelerator can be advantageously used for manypreparations of topical agents which are expected to exhibit thepharmacological effect upon application to skin, hair, nails, and thelike to be absorbed for example, from a liquid spraying agent, a lotion,an ointment, a cream, a gel, a sol, an aerosol, a cataplasm, a plaster,a tape preparation, and the like.

Further, in a transmucosal administration, the percutaneous absorbentpreparation of the present invention is prepared using theabove-mentioned transmucosal absorption accelerator either as it is, or,by formulating the same in various forms of preparations fortransmucosal administration, for example, suppositories for rectal andvaginal administration, an ointment, a soft gelatin capsule, a buccaltablet, a perlingual tablet, a nose drop, or a spraying agent for nasalmucous membrane or buccal mucous membrane, and, if necessary, furtheradding desired carriers, vehicles, etc. for preparations and makingpreparations in a conventional manner. In addition, the preparation fortransmucosal absorbing activity may contain, for example, ether typenon-ionic surfactants, enamine derivatives of phenylglycine,N-acylcollagen peptides, sodium salts of medium chain fatty acids,saponins, and so forth.

It is preferred that the percutaneous absorption accelerator of thepresent invention be formulated, as the effective component, in anamount of 0.001 to 10% by weight, particularly 0.1 to 8% by weight, intothe preparation for percutaneous administration, based on the totalamount of the preparation, as an aid for percutaneous absorption.Further, in the case of using the percutaneous absorption as the basefor percutaneous absorption, it is also possible to formulate the samein an amount of 10% by weight or more.

Examples in which pharmaceutical effects increase by the utilization ofthe percutaneous absorbent preparation of the present invention astopical agents include steroid anti-inflammatory agents, such asprednisolone, and dexamethason, non-steroid anti-inflammatory agents,such as indomethacin, fulfenamic acid, and mefenamic acid, anti-histamicagents, such a tripernamine, insaibenzyl, chlorpheniramine,diphenhydramine, and promethazine; sulfa agents, such assulfamonomethoxine, and sulfamethizole; and antibiotics, such aspenecillan, cephalosporin, erythromycin, tetracyclin, chloramphenicol,and streptomycin; anti-fungal agents, such as napthiomate, andclotrimazole; anti-malignant tumor agents, such as 5-fluorouracil,cyclophosphamide, busulfan, and actinomycin; analgesics, such asmorphine, codeine, nalorphine, pentazocine, aspirin, acetanilide, andaminopyrine; preparations of prostaglandins; hypnotics andtranquilizers, such as barbital, and thiopental; psychotropic agents,such as chlorpromazine, reserpine, and chlordiazepoxide; anti-epilepticagents; anti-Parkinson's syndrome agents, such as chlorzoxazone, andrevodopa; cardiotonic agents, such as digitoxin, and digoxin;anti-arrhythmic agents, such as procainamide hydrochloride, andpropranolol hydrochloride; anti-angina pectoris agents, such asdipyridamole, and amyl nitrite; anti-hypertension agents, such asreserpine, and guanethidine sulfate; UV inhibitors, such asp-aminobenzoate esters; agents for preventing the formation of melanine,such as hydroquinone, vitamin C esters, and p-hydroxycinnamate; PUVAtreating agents against psoriasis, such as 8-methoxypsoralen; vitamins,such as vitamin A, estradiol, and methyltestosterone; diagnostics;allergens for patch test; vermicides, insecticides; moisturizers;keratin softening agents; hair dyes; and the like, but are notexhaustive thereof.

Further, the percutaneous absorbent preparation for the topical agent ofthe present invention is also effective for many drugs, agriculturalchemicals, growth hormones, etc. for which pharmacological effects areexpected by applying the same to animals, insects, plants, and so on tobe absorbed therein.

Examples in which pharmaceutical effects increase by the utilization ofthe transmucosal absorption of the present invention includepharmacologically active polysaccharide substances such as heparin,dextran sulfate, pentosan sulfate (heparinoid), chondroitin sulfate andsalts thereof, glucoamylase inhibitor; peptide type anti-tumorsubstances, such as bleomycin, neocarzinostan, and L-asparginase; enzymepreparations, such as trypsin, chemotrypsin, bromelain, papain,protenase, peroxidase, nagase, proctase, serratiopeptidase, seaprose,lysozyme, plasmin, urokinase, cytochrome C, hyaluronidase,fibrinolysine, thrombin, callidin, callikrein, plasmin, glucose oxidase,B-galactosidase, fytin, desoxyribonuclease, choline esterase, pronase,and pancreatin; peptide hormones, such as calcitonin, parathormone,relaxin, insulin, glucagon, prolactin, adrenocorticotropin (ACTH),gonaotropic hormone, thyrotropin (TSH), growth hormone (BGH),luteinizing hormone (LH), follicle-stimulating hormone (FSH), oxytocin,vasopressin, anti-diuretic hormone, coherin, melanocyte-stimulatinghormone (MSH), gastrin, tetragastrin, pentagastrin, secretin,pancreozymin, cholecystokinin, Substance P, gonadotropin (HCG), andvasopressin; inhibitors for peptide hormone releasing factors, such asadrenocorticotropic hormone releasing factor (ACTH-RH),follicle-stimulating hormone releasing factor (FSH-RH), growth hormonereleasing factor (GH-IH), luteinizing hormone releasing factor (LH-RH),prolactin releasing factor (PR-RH), prolactin inhibiting factor (PR-IH),and thyroid-stimulating hormone releasing factor (TSH-RH);polynucleotides, such as polyribonucleotide, complex of polyinocinicacid and cytidylic acid, complex of polyadenylic acid and polyuridilicacid, and polydeoxyribonucleotide; insulin secretion-activating protein(IAP), pancreas-basic trypsin inhibitor, antipain hydrochloride,chymostatin A, elastatinal, pepstatin A, polylysine, polyornithine,polyethylenimine, and polyvinylamine; steroid anti-inflammatory agents,such as prednisolone, and dexamethason; non-steroid anti-inflammatoryagents, such as indomethacin, fulfenamic acid, and mefenamic acid;anti-histamic agents, such triperenamine, insaibenzyl, chlorpheniramine,diphenhydramine, and promethazine; sulfa agents, such assulfamonomethoxine, and sulfamethizole; antibiotics, such as penicillin,cephalosporin, erythromycin, tetracyclin, chloramphenicol, andstreptomycin; anti-malignant tumor agents, such as 5-fluororacil,cyclophosphamide, bulsulfan, and actinomycin; analgesics, such asmorphine, codeine, nalophine, pentazocine, aspirin, acetanilide, andaminopyrine; preparations of prostaglandine; hypnotics andtranquilizers, such as barbital, and thiopental; psychotropic agents,such as chlorpromazine, reserpine, and chlordiazepoxide; anti-epilepticagents; anti-Parkinson's syndrome agents, such as chlorzoxazone, andrevodopa; cardiotonic agents, such as digitoxin, and digoxin;anti-arrhythmic agents, such as procainamide hydrochloride, andpropranolol hydrochloride; anti-angina pectoris agents, such asdipyridamole, and amyl nitrite; and anti-hypertension agents, such asreserpine, and guanethidine sulfate.

In the present percutaneous absorbent preparation, such apharmaceutically effective component may be incorporated in apharmaceutically effective amount according to the particular object towhich the preparation is to be applied.

In the ether derivative used in the present invention, the structure canbe appropriately chosen to control the balance between a hydrophilicproperty and an oleophilic property so that it is possible to preparethe ether derivative in any base having either a hydrophilic oroleophilic property. As a result, the ether derivative having a highsolubility for various pharmaceutically effective components can bechosen according to the present invention. It is thus possible to designtopical agents having good handling and high percutaneous absorption bydissolving difficultly soluble pharmaceutically effective components inhydrophilic bases in a high concentration.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 shows a change in blood concentration of salicylic acid when theaspirin suppository of the present invention and the control aspirinsuppository containing no transmucosal absorption accelerator wereadministered to rabbits.

PREFERRED EMBODIMENTS

Next, the present invention will be described with reference to theexamples below but it is not deemed to be limited only to theseexamples.

TEST EXAMPLE 1

Japanese white male rabbits weighing about 2.5 kg, fasted for 24 hours,were fixed at the back, and each of solutions shown in Table 1 wasadministered to the rectum of about 2.5 cm from the anus using a tube.Cannule was inserted into the femoral vein of the hind leg to collectabout 0.2 ml each of blood in every fixed time interval. Blood sugarlevel was measured using destrostick. Change in blood sugar level wasdetermined with the passage of time, as the blood sugar level prior toadministration being rendered 100%. The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                       Rate of Change in Blood Sugar Level before                                    Administration (%)                                         Specimen           15 mins.                                                                           30 mins.                                                                           45 mins.                                                                           60 mins.                                                                           90 mins.                                                                           120 mins.                         __________________________________________________________________________    Control:                                                                      Physiological saline                                                                         0.75 g                                                         Ethanol        0.25 g                                                                            +10.2                                                                              +12.5                                                                              +11.2                                                                              +11.2                                                                              +12.2                                                                              +18.0                             Insulin        10/kg                                                          25% Ethanol solution                                                                             +5.0 +12.9                                                                              +11.5                                                                              +4.8 +1.5 +2.7                              1-O--n-Dodecyl-3-O--methyl-                                                   2-O--2',3'-dihydroxy-                                                                        1 g +6.5 +10.2                                                                              +9.8 +9.5 +9.5 +10.2                             propylglycerol                                                                This Invention                                                                Physiological saline                                                                         0.70 g                                                         Ethanol        0.25 g                                                         Insulin        10/kg                                                                             -13.4                                                                              -18.6                                                                              -25.2                                                                              -27.6                                                                              -25.8                                                                              -22.4                             1-O--n-Dodecyl-3-O--methyl-                                                   2-O--2',3'-dihydroxy-                                                                        0.05 g                                                         propylglycerol                                                                Physiological saline                                                                         0.65 g                                                         Ethanol        0.25 g                                                         Insulin        10/kg                                                                             -19.2                                                                              -28.9                                                                              -32.7                                                                              -28.0                                                                              -19.5                                                                              -18.2                             1-O--n-Dodecyl-3-O--methyl-                                                                  0.1 g                                                          2-O--2',3'-dihydroxypropyl-                                                   glycerol                                                                      Physiological saline                                                                         0.65 g                                                         Ethanol        0.25 g                                                         Insulin        10/kg                                                                             -17.8                                                                              -18.3                                                                              -24.5                                                                              -28.6                                                                              -21.9                                                                              -19.8                             1-O--Methyl-branched                                                          isostearyl-3-O--methyl-                                                                      0.1 g                                                          2-O--2',3'-dihydroxy-                                                         propylglycerol                                                                __________________________________________________________________________

TEST EXAMPLE 2

To a mixture of 1.4 g of1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 4.5 g ofethanol was added a 17 U/ml insulin solution in physiological salineand, the mixture was made 10 g in total to prepare a preparation fornasal spraying. The preparation was administered to the nasal cavity ofmale rabbits, weighing about 2.5 kg, fasted for 24 hours and fixed atthe back, at a dose of 1 U/rabbit. Insulin in serum was quantitativelydetermined by enzyme immunoassay. For control, a preparation obtained bysupplementing physiological saline for the above-mentioned1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol was used. Theresults are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Concentration of Insulin in Serum (μU/ml)                                  0      20 mins.                                                                           40 mins.                                                                           60 mins.                                                                           90 mins.                                                                           120 mins.                                                                          180 mins.                                     __________________________________________________________________________    Control                                                                            5 8    12   12   12   14   14                                            This 7 261  227  95   78   31   28                                            Invention                                                                     __________________________________________________________________________

EXAMPLE 1

Topical agents containing indometacin shown below were prepared andpercutaneous absorption was examined with the topical agents. Theresults are shown in Table 3.

Preparation

Preparation 1 of the present invention:

An ointment obtained by incorporating 3 g of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97 g ofa commercially available gel-like topical agent containing 1 wt % ofindomethacin, Inteban ointment (made by Sumitomo Chemical Industry Co.,Ltd.).

Preparation 2 of the present invention:

An ointment obtained by incorporating 3 g of 1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97 g of acommercially available gel-like topical agent containing 1 wt % ofindomethacin, Inteban ointment (made by Sumitomo Chemical Industry Co.,Ltd.).

Preparation 3 of the present invention:

An ointment obtained by incorporating 3 g of 1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol into 97 g of acommercially available gel-like topical agent containing 1 wt % ofindomethacin, Inteban ointment (made by Sumitomo Chemical Industry Co.,Ltd.).

Preparation 4 of the present invention:

An ointment obtained by incorporating 3 g of1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol into 97 g of acommercially available gel-like topical agent containing 1 wt % ofindomethacin, Inteban ointment (made by Sumitomo Chemical Industry Co.,Ltd.).

Preparation 5 of the present invention:

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g ofethanol to make 100 g.

Preparation 6 of the present invention:

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of 1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g ofethanol to make 100 g.

Preparation 7 of the present invention:

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of 1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol and 45 g ofethanol to make 100 g.

Preparation 8 of the present invention:

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 45 g ofethanol to make 100 g.

Comparative preparation 1

A commercially available gel-like topical agent containing 1 wt % ofindomethacin, Inteban® ointment (made by Sumitomo Chemical Industry,Co., Ltd.).

Comparative preparation 2

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of N,N-diethyl-m-toluamide and 45 g of ethanolto make 100 g.

Comparative preparation 3

A liquid topical agent obtained by adding purified water to a mixture of1 g of indomethacin, 14 g of dimethylsulfoxide and 45 g of ethanol tomake 100 g.

METHOD Test of percutaneous absorption of indomethacin:

Seven (7) Japanese white female rabbits weighing about 3 kg were used asone group. The topical agents of the present invention and thecomparative preparations were applied onto the normal abdominal skin (10cm×14 cm) of the rabbits in each group, from which the body hair wascut, respectively, at a dose corresponding to 20 mg of indomethacin.Blood was collected from the vein of the ear after 4, 10 and 20 hoursand, blood concentration of indomethacin was measured.

                  TABLE 3                                                         ______________________________________                                                      Maximum Concentration in                                        Preparation   Serum (Cmax; ng/ml)                                             ______________________________________                                        This invention                                                                            1     540                                                         "           2     510                                                         "           3     500                                                         "           4     420                                                         Comparative                                                                   Preparation 1     95                                                          This invention                                                                            5     1900                                                        "           6     1750                                                        "           7     1550                                                        "           8     1230                                                        Comparative                                                                   Preparation 2     190                                                         "           3     150                                                         ______________________________________                                    

As is clear from the results described above, topical agents 1 to 8 ofthe present invention all showed extremely high percutaneous absorptionof indomethacin as compared to the comparative preparations. Inparticular, the topical agent of the present invention obtained byformulating 1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerolas a percutaneous absorption accelerator showed extremely highpercutaneous absorption of indomethacin.

EXAMPLE 2

With respect to the topical agents of the present invention, thepharmacological effect was examined according to the inhibition ofcarrageenin caused edema on the the paw of the rat. The results areshown in Table 4.

METHOD:

Wistar male 10 rats, weighing about 110 g, were used as one group. Thevolume of the right rear paw of the rats in each group was previouslymeasured using a branched glass container. A 1% carrageenin aqueoussolution was subcutaneously injected to the right rear paw sole in adose of 0.125 ml. Immediately thereafter 0.3 g of indomethacin topicalagents were applied to the skin of the right rear paw sole. In thecontrol group, carrageenin alone was injected. Then, the volume of therear paw was measured every 90 minutes, which was continued until 6hours after. The rate of edema and the inhibition rate of edema werecalculated as described below. ##EQU1##

                  TABLE 4                                                         ______________________________________                                                    Inhibition Rate of Edema (%)                                      Preparation  1.5 hr    3.0 hrs 4.5 hrs 6.0 hrs                                ______________________________________                                        This invention                                                                           5     52.6      52.7  53.7    56.0                                 "          8     23.7      37.4  40.8    50.3                                 Comparative                                                                   Preparation                                                                              1     10.5      3.9   3.5     2.0                                  ______________________________________                                    

As is clear from the results described above, the topical agents of thepresent invention showed an extremely high rate of preventing the edemacaused by carrageenin due to the pharmacological effect of indomethacin,as compared to the comparative preparation. In particular, the topicalagent obtained by formulating1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol as apercutaneous absorption accelerator showed an extremely highpharmacological effect of indomethacin.

EXAMPLE 3

A topical agent containing mefenamic acid shown below was prepared andthe percutaneous absorption was tested. The results are shown in Table5.

Preparation 9 of the present invention:

Mefenamic acid, 1 g, was incorporated in a mixture of 10 g of propyleneglycol, 5 g of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol and 30 g ofethanol. The mixture was added to a swollen mixture of 1 g of"HIVISWAKO-104" (made by Wako Pure Chemical Industries, Ltd.,carboxymethyl polymer) in 20 g of purified water. After the mixture washomogeneously mixed, 3 g of 2% ammonia water was added thereto whilestirring and, purified water was further added thereto to make 100 g toobtain a gel ointment.

Comparative preparation 4

Mefenamic acid, 1 g, was incorporated in a mixture of 15 g of propyleneglycol and 30 g of ethanol. The mixture was added to a swollen mixtureof 1 g of "HIVISWAKO-104" (made by Wako Pure Chemical Industries, Ltd.,carboxymethyl polymer) in 20 g of purified water. After the mixture washomogeneously mixed, 3 g of 2% ammonia water was added thereto whilestirring and, purified water was further added thereto to make 100 g toobtain a gel ointment.

METHOD: Test for percutaneous absorption of mefenamic acid:

Seven (7) Japanese white female rabbits weighing about 3 kg were used asone group. The topical agents of the present invention and thecomparative preparations were applied onto the normal abdominal skin (10cm×14 cm) of the rabbits in each group, from which the body hair wascut, respectively, at a dose corresponding to 50 mg of mefenamic acid.Blood was collected from the vein of the ear after 4, 10 and 20 hoursand, blood concentration of mefenamic acid was measured.

                  TABLE 5                                                         ______________________________________                                                  Concentration of Mefenamic Acid                                               in Serum (C; μg/ml)                                              Preparation 4 hrs        10 hrs  20 hrs                                       ______________________________________                                        This invention 9                                                                          4.9          5.1     4.7                                          Comparative                                                                   Preparation 1.8          1.1     0.4                                          ______________________________________                                    

As is clear from the results described above, the topical agent of thepresent invention showed extremely high percutaneous absorption ofmefenamic acid, as compared to the comparative preparation.

EXAMPLE 4

Cataplasms shown below were prepared and, the percutaneous absorption ofmethyl salicylate was tested. The results are shown in Table 6.

Preparation:

Preparation 10 of the present invention:

To 10 parts (weight basis, hereafter the same) of gelatin were added 35parts of water. The mixture was warmed to 70° C. to dissolve gelatintherein. To this solution were added 12 parts of titanium oxide, 10parts of glycerol, 10 parts of sorbitol and 10 parts of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol. Then, 5parts of self-cross linkable sodium polyacrylate (prepared in accordancewith Example 1 of Published Examined Japanese Patent Application30710/79) and 5 parts of sodium carboxymethyl cellulose were added tothe mixture. Further 3 parts of a drug (drug mixture obtained byformulating 1-methanol, d-camphor and methyl salicylate in a weightratio of 5:1:4) were added thereto and the mixture was kneaded to obtaina cataplasm paste composition. The composition was coated on a lintsheet. A polypropylene film was applied to the paste surface, which wascut into an appropriate size to obtain a cataplasm.

Preparation 11 of the present invention:

A cataplasm similar to Preparation 10 of the present invention wasprepared by formulating 10 parts of 1-O-methylbranchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol instead of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol inPreparation 10 of the present invention, 10 parts of glycerol and 10parts of sorbitol.

Comparative preparation 5

A cataplasm similar to Preparation 10 of the present invention wasobtained except that 15 parts of glycerol and 15 parts of sorbitol wereused in place of 10 parts of glycerol and 10 parts of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.

METHOD: Test for percutaneous absorption of methyl salicylate:

Seven (7) Japanese white female rabbits weighing about 3 kg were used asone group. Each sheet of the cataplasms of the present invention and thecomparative preparation, in which 1.2 wt. % of methyl salicylate wasformulated, were applied to the normal abdominal skin (10 cm×14 cm) ofthe rabbits in each group, from which the body hair was cut,respectively. Blood was collected from the vein of the femur after 3, 6,10, 20 and 30 hours and, blood concentration of methyl salicylate wasmeasured.

                  TABLE 6                                                         ______________________________________                                                     Maximum Concen-                                                               tration in Serum                                                                              Reaching Time                                    Preparation  (Cmax; μg/ml)                                                                              (Tmax; hr)                                       ______________________________________                                        This invention                                                                           10    47              10                                           "          11    41              10                                           Comparative                                                                   Preparation                                                                              5     14              6                                            ______________________________________                                    

As is clear from the results above, the cataplasms of the presentinvention all showed extremely high percutaneous absorption of methylsalicylate, as compared to the cataplasm for comparison. In particular,the cataplasm of the present invention obtained by formulating1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol as thepercutaneous absorption accelerator showed extremely high percutaneousabsorption of methyl salicylate.

EXAMPLE 5

Topical agents containing naphthiomate shown below were prepared and,the percutaneous absorption was tested. The results are shown in Table7.

Preparation:

Preparation 12 of the present invention:

A mixture of 1 g of naphthiomate, 5 g of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol, 14 g ofglycerol triacetate 30 g of methyl ethyl ketone and 50 g of ethanol wasmade a liquid topical agent.

Comparative preparation 6

A mixture of 1 g of naphthiomate, 19 g of glycerol triacetate 30 g ofmethyl ethyl ketone and 50 g of ethanol was made a liquid topical agent.

METHOD: Test for percutaneous absorption of naphthiomate:

Wistar-strain male 10 rats, weighing about 150 g, were used as 1 group.The topical agent was applied to the normal back skin (5 cm×4 cm) of therats of each group, from which the body hair was cut, in a dosecorresponding to 2 mg of naphthiomate. Blood was collected from theabdominal main artery after 10 hours and, blood concentration ofnaphthiomate was measured.

                  TABLE 7                                                         ______________________________________                                                     Concentration of naphthiomate in serum                           Preparation  (C; ng/ml)                                                       ______________________________________                                        This invention                                                                           12    29.5                                                         Comparative                                                                   Preparation                                                                              6     9.3                                                          ______________________________________                                    

As is clear from the results described above, the topical agent preparedin the example showed extremely high percutaneous absorption ofnaphthiomate, as compared to the comparative example.

EXAMPLE 6 Aspirin Suppository:

(1) Pharmacopeial aspirin: 1 g

(2) 1-O-n-Dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol: 0.5 g

(3) Homotex (made by Kao Soap Co., Ltd., medium chain fatty acidtriglyceride): 8.5 g

(1) to (3) were thoroughly agitated and mixed and, 1 g each of themixture was filled up in a soft gelatin capsule to prepare an aspirinsuppository.

The aspirin suppository of Example 6 was administered to male rabbitsweighing about 3 kg and, change in blood concentration of salicylic acidwas measured. For control, the following was used.

Control: suppository containing 100 mg of pharmacopeial aspirin inHomotex as a base.

The results are shown in FIG. 1.

EXAMPLE 7 Indometacin Suppository:

(1) Pharmacopeial indometacin: 1.5 g

(2) 1-O-Methyl-branchedisostearyl-3-methyl-2-O-2',3'-dihydroxypropylglycerol: 0.5 g

(3) Homotex (supra): 8.0 g

(1) to (3) were thoroughly agitated and mixed and, 1 g each of themixture was filled up in a soft gelatin capsule to prepare anindometacin suppository.

EXAMPLE 8

In a manner similar to Example 6, an aspirin suppository was preparedusing 1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.

EXAMPLE 9

In a manner similar to Example 7, an indomethacin suppository wasprepared using1-O-n-dodecyl-3-O-methyl2-O-2',3'-dihydroxypropylglycerol.

EXAMPLE 10 Insulin Suppository:

(1) Solution of 100 IU of insulin in 0.5 ml of a 6% aqueous acetic acidsolution: 0.5 g

(2) 1-O-n-Dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol: 0.5 g

(3) Homotex: 9.0 g

After (1) to (3) were thoroughly agitated to disperse, 1 g each of thedispersion was filled up in a soft gelatin capsule to prepare an insulinsuppository.

EXAMPLE 11 Insulin Spraying Agent for Nasal Use:

(1) Solution of 1000 IU of insulin in 2.0 ml of a 6% aqueous acetic acidsolution: 2 g

(2) 1-Methyl-branched isostearyl-3-O-methyl-2-O-2'3-dihydroxypropylglycerol: 2 g

(3) Ethanol: 6 g

(4) Physiological saline solution: 90 g

(1) to (4) were thoroughly mixed, and, the mixture was filled up in apump sprayer to make an insulin spraying agent for nasal use.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

What is claimed is:
 1. A percutaneous absorbent preparation fortransdermal or transmucosal absorption of a pharmaceutically activesubstance, comprising:an effective amount of indomethacin; and anabsorption accelerator selected from the group consisting of1-O-n-decylglycerol, 1-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-3-O-2',3'-dihydroxypropylglycerol, 1-O-methyl-branchedisostearyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1O-n-dodecyl-2-O-n-butyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-2O-methyl-3O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-2-O-n-butyl-3-O-2',3'-dihydroxypropyl-glycerol,1-O-methyl-branchedisostearyl-2-O-methyl-3-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-2-O-n-octyl-3-O-2',3'-dihydroxypropylglycerol;1O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-3-O-methyl-2-O-2',3'dihydroxypropylglycerol,1-O-n-dodecyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-dodecyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-tetradecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-hexadecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-n-octadecenyl-3-O-n-butyl-2-O-2',3'-dihydroxypropyl-glycerol,1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol, and1-O-methyl-branchedisostearyl-3-O-n-octyl-2-O-2',3'-dihydroxypropylglycerol.
 2. Thepreparation of claim 1, wherein said accelerator is present in an amountof from 0.001 to 10% by weight of said preparation.
 3. The preparationof claim 1, which further contains at least one member selected from thegroup consisting of ether type non-ionic surfactants, enaminederivatives of phenylglycine, N-acylcollagen peptides, and saponins. 4.The preparation of claim 1, which is in the form of a liquid, a lotion,an ointment, a cream, a gel, a sol, an aerosol, a cataplasm, a plaster,or a tape preparation.
 5. A method for transdermal or transmucosalabsorption of which indomethacin comprises administering an effectiveamount of the percutaneous absorbent preparation of claim 1 to the skinor a mucous membrane of a subject.
 6. The preparation of claim 4, whichis in the form of an ointment comprising (a) one member selected fromthe group consisting of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol, and1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol; and (b) atopical agent containing 1 wt % of indomethacin.
 7. The preparation ofclaim 4, which is in the form of a liquid topical agent comprising (a)one member selected from the group consisting of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol, and1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol; (b)indomethacin; (c) ethanol; and (d) water.
 8. The preparation of claim 1,wherein said accelerator is selected from the group consisting of1-O-n-dodecyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol,1-O-methyl-branchedisostearyl-3-O-n-butyl-2-O-2',3'-dihydroxypropylglycerol, and1-O-n-octyl-3-O-methyl-2-O-2',3'-dihydroxypropylglycerol.